Major depression is hypothesized to be associated with reduced serotonergic function. Effects on the serotonergic system appear involved in the mechanism of antidepressant action of selective serotonin reuptake inhibitors (SSRls) and ECT. Animal and clinical studies suggest that ECT and antidepressant drugs enhance overall serotonergic transmission. Serotonin depletion reverses the antidepressant effect of drugs. We hypothesize that there is reduced brain serotonin function in depression and that enhanced serotonin effects may be central to antidepressant action of SSRls and perhaps ECT. We have developed a method for assessing central serotonergic function by a fenfluramine (indirect serotonin agonist) challenge using regional cerebral glucose uptake (positron emission tomography (PET) imaging of l8FDG) and the response of plasma prolactin (PRL). In the first year of this project, we will study the time course of serotonin brain response, the validity and sensitivity of the method using a tryptophan depletion protocol, and its test-retest stability. Studying central serotonergic function in this way allows us to evaluate both the magnitude and location in the brain of altered serotonin responsivity. We propose to study: 1) serotonergic responses in patients suffering from a Major Depressive Episode, with melancholia compared to healthy controls in order to determine by cross-sectional contrast the alteration in serotonergic function in the disease state and how it relates to treatment outcome; 2) whether the direction of change with treatment is in the direction of normality and how treatment effect on regional brain serotonin responses correspond to areas of altered serotonin function before treatment; 3) the effect of ECT on the serotonergic system in drug-free patients with melancholia in comparison to the effects of the selective serotonin reuptake inhibitor paroxetine. We have found blunted responses to fenfluramine in the prefrontal cortex of untreated depressed patients using this method. We hypothesize that both ECT and paroxetine will enhance effects of fenfluramine on regional glucose uptake in the prefrontal cortex. Thus, we will measure regional correspondence of the brain serotonin deficits in depression and the effect of a course of ECT or SSRI drugs upon the serotonergic system. Elucidation of the mechanism and locus of antidepressant action of ECT compared to SSRIs may ultimately lead to improved antidepressant medication and better understanding of the pathophysiology of depression.